Terminally differentiated myeloid cells are essential to normal function of both the innate and adaptive immune systems. These cells protect organisms from pathogens, eliminate dying cells and mediate tissue remodeling. However, cancer pathologically alters myeloid cells into potent immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs) that enable cancer progression and spread. The tumor-mediated alteration of myeloid cells is not confined to the tumor, but is a systemic phenomenon (Gabrilovich, 2012, Nat Rev Immunol, 12:253-68). Soluble factors released by the tumor act at distant sites that include bone marrow and spleen, where they alter macrophages and granulocytes to become immunosuppressive and accumulate within the tumor. Peripheral blood from advanced cancer patients have much higher MDSC levels compared to healthy donors (P<0.001), who have near undetectable levels (Alfaro, 2016, Clin Cancer Res, 22:3924-36). The MDSC lifespan is short (24-96 hours), and tumors require continuous MDSC resupply to maintain homeostasis of tumor MDSC populations (Condamine, 2014, J Clin Invest, 124:2626-39). Thus, an effective strategy to abrogate MDSC activity in the tumor microenvironment may be to prevent MDSC arrival to tumors, which has been shown to deplete tumors of MDSCs.
Chemokines are chemotactic proteins that have the potential to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. Chemokines are typically low molecular mass (7-9 kD) proteins that can be divided into four subfamilies: CC (or β-chemokines), CXC, C (or γ-chemokines) and CX3C (or δ-chemokines). The CXC-chemokines (i.e., the ligands for CXCR1 and/or CXCR2) include, but are not limited to, interleukin-8 (IL-8, CXCL8), GROα (CXCL1), GROβ (CXCL2), GROγ (CXCL3), ENA-78 (CXCL5), GCP-2 (CXCL6), and NAP-2 (CXCL7). IP-10. Tumor secreted chemokines CXCL1, CXCL2 and CXCL5 recruit MDSCs to tumors (or a pre-metastatic niche) in numerous mouse tumor models (Condamine, 2015, Annu Rev Med, 66: 97-110). These chemokines all bind chemokine receptor CXCR2. Tumor secreted CXCL8 (IL-8) also recruits MDSCs (Mestas, 2004, J Immunol, 172:2731-38; Ben-Baruch, 2012, Cancer Microenviron, 5:151-64), which signals via both CXCR1 and CXCR2 receptors (Rot, 2004, Annu Rev Immunol, 22: 891-928). Thus, there is a clear therapeutic advantage to find a means to target both CXCR1 and CXCR2 to block MDSC recruitment during cancer growth and metastasis.